The objective is to characterize monoaminergic (MA) projections to cerebral cortex in terms of anatomic and chemical features that are important determinants of function. This study will provide a definitive account of the neurotransmitters and the cortical distribution of projections from the raphe nuclei and locus coeruleus. A central theme of this project is to test a new hypothesis that the raphe nuclei send multifocal projections to small patches of cortex; thus, clusters of adjacent neurons may selectively influence specific sets of cortical areas. Four sets of inter-related experiments are proposed. 1) Anterograde axonal transport of a lectin (PHA-L) will be employed to characterize and compare the terminal distribution of raphe-cortical and of coeruleo-cortical axons. 2) The transmitters and projections of non-5-HT neurons in the raphe nuclei will be determined. To this end, anterograde and retrograde transport methods will be combined with transmitter immunocytochemistry in order to identify the neurotransmitters of cortically projecting raphe neurons and their axon terminals. 3) The preliminary finding that 5-HT cells in different raphe nuclei give rise to highly distinctive axon terminals will be verified, and electron microscopy will be used to determine whether the specialized varicosities reflect differences in synaptic morphology and organization. 4) The intracortical localization of 5-HT receptors will be mapped and correlated with regional and laminar patterns of 5-HT innervation. [The project employs highly sensitive neuroanatomic methods for anterograde and retrograde axonal transport in combination with transmitter immunocytochemistry, receptor autoradiography and electron microscopy.] This study should provide new information of clinical importance concerning the functional organization of MA neurons. These neuronal projections are thought to regulate cortical excitability and to be involved in several neuro-psychiatric disorders, particularly the dementias and affective disorders. Moreover, these experiments should help to elucidate the effects of particular drugs of abuse recently shown to be selectively cytotoxic to 5-HT axons.